Use of hydroxyeicosatetraenoic acid derivatives in intraocular surgery

ABSTRACT

The use of HETE derivatives in intraocular surgery (e.g., cataract surgery) is disclosed. The HETE derivatives protect and maintain the corneal endothelium.

[0001] This application claims priority to U.S. Provisional Application,U.S. Ser. No. 60/242,501 filed Oct. 23, 2000.

[0002] The present invention is directed to the use ofhydroxyeicosatetraenoic acid derivatives during intraocular surgery. Inparticular, the invention relates to the use of such derivatives for theprotection of the corneal endothelium during intraocular surgery.

BACKGROUND OF THE INVENTION

[0003] Mucins are proteins which are heavily glycosylated withglucosamine-based moieties. Mucins provide protective and lubricatingeffects to epithelial cells, especially those of mucosal membranes.Mucins have been shown to be secreted by vesicles and discharged on thesurface of the conjunctival epithelium of human eyes (Greiner et al.,Mucous Secretory Vesicles in Conjunctival Epithelial Cells of Wearers ofContact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846(1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctivain Man, with Special Reference to the Production of Mucous from aNon-Goblet-Cell Source, British Journal of Ophthalmology, volume 65,pages 833-842 (1981)). A number of human-derived mucins which reside inthe apical and subapical corneal epithelium have been discovered andcloned (Watanabe et al., Human Corneal and Conjunctival EpitheliaProduce a Mucin-Like Glycoprotein for the Apical Surface, InvestigativeOphthalmology and Visual Science, volume 36, number 2, pages 337-344(1995)). Recently, Watanabe discovered a new mucin which is secreted viathe cornea apical and subapical cells as well as the conjunctivalepithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2,pages 337-344 (1995)). These mucins provide lubrication, andadditionally attract and hold moisture and sebaceous material forlubrication and the corneal refraction of light.

[0004] Mucins are also produced and secreted in other parts of the bodyincluding lung airway passages, and more specifically from goblet cellsinterspersed among tracheal/bronchial epithelial cells. Certainarachidonic acid metabolites have been shown to stimulate mucinproduction in these cells. Yanni reported the increased secretion ofmucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid(“HETE”) derivatives (Yanni et al, Effect of Intravenously AdministeredLipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness,International Archives of Allergy And Applied Immunology, volume 90,pages 307-309 (1989)). Similarly, Marom has reported the production ofmucosal glycoproteins in human lung by HETE derivatives (Marom et al.,Human Airway Monohydroxy-eicosatetraenoic Acid Generation and MucousRelease, Journal of Clinical Investigation, volume 72, pages 122-127(1983)).

[0005] Agents claimed for increasing ocular mucin and/or tear productioninclude vasoactive intestinal polypeptide (Dartt et. al., Vasoactiveintestinal peptide-stimulated glycocongjugate secretion fromconjunctival goblet cells. Experimental Eye Research, volume 63, pages27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulatessecretion of mucin-like glycoproteins by corneal epithelium in vitro andprotects corneal epithelium from dessication in vivo, Experimental EyeResearch, volume 65, pages 569-574 (1997)), liposomes (U.S. Pat. No.4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulatinghormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S.Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5,455,265). None ofthese agents, however, have been reported to have an effect on thecorneal endothelium.

[0006] U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositionscontaining HETE derivatives and methods of using them topically fortreating dry eye. Yanni et al. discovered that compositions comprisingHETE derivatives increase ocular mucin secretion and are thus useful intreating dry eye. This patent does not disclose the use of the HETEderivatives during intraocular surgery for the protection of the cornealendothelium.

[0007] During intraocular surgery, such as cataract surgery, the cornealendothelium is susceptible to damage by physical contacts withinstrumentation or implants and fluid turbulence and ultrasonicdisturbance during phacoemulsification. The corneal endothelium does notregenerate. Corneal endothelial cell damage can lead to a reduction incorneal endothelial cell density and an impairment of ion-pumpingfunction, both of which can lead to corneal edema and visual impairment.Irrigating solutions containing nutrients (ions, glucose, etc.) and/oranti-oxidants have been proposed to maintain or protect the cornealendothelium. Additionally, viscoelastics are used to provide a physicalbarrier in order to prevent contact damage.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to methods of using of HETEderivatives to maintain and protect the corneal endothelium duringintraocular surgery. The invention also relates to compositionscontaining HETE derivatives where the compositions are intended for useduring intraocular surgery. Although not wishing to be bound by anytheory, it is believed that the HETE derivatives maintain and protectthe corneal endothelium by stimulating mucin secretion in the cornealendothelium.

DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein, “HETE derivative” means a compound of formulasI-XI.

[0010] I-III:

[0011] wherein:

[0012] X is OR or NHR′;

[0013] R is H, a cationic pharmaceutically acceptable salt moiety,substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,arylalkyl, wherein the substitution is made with a moiety selected fromthe group consisting of: alkyl, halogen, hydroxy and functionallymodified hydroxy;

[0014] R′ is H, substituted or unsubstituted alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is madewith a moiety selected from the group consisting of: alkyl, halogen,hydroxy and functionally modified hydroxy; and

[0015] Y is

[0016] wherein

[0017] R″ is H or C(O)R;

[0018] wherein:

[0019] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂-Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein:

[0020] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0021] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R²and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0022] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

[0023] Hal is F, Cl, Br or I;

[0024] SR²⁰ comprises a free or functionally modified thiol group;

[0025] R²¹ is H, or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0026] K is C₂-C₈ alkyl, alkenyl, or alkynyl, or a C₃-C₈ allenyl group;

[0027] A and X are the same or different and are a direct bond, CH₂,NR⁷, O, or S, with the proviso that at least one of A and X is NR⁷, O,or S;

[0028] B is H, or BB together comprises a double bonded O, S, or NR^(8,)with the proviso that BB comprises a double bonded O, S, or NR⁸ when Aand X are the same or different and are NR⁷, O, or S; wherein:

[0029] NR⁷ and NR⁸ are the same or different and comprise a functionallymodified amino group, e.g., R⁷ and R⁸ are the same or different and areH, alkyl, cycloalkyl, aryl, aralkyl, acyl, OH, or alkoxy;

[0030] p is 0 or 1;

[0031] D-E, G-H are the same or different and are CH₂CH₂, CH═CH, or C≡C;and

[0032] Y is C(O) (i.e. a carbonyl group) or Y is

[0033] wherein

[0034] R⁹O constitutes a free or functionally modified hydroxy group;

[0035] wherein:

[0036] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where:

[0037] R is H or a pharmaceutically acceptable cation, or CO₂R forms apharmaceutically acceptable ester moiety;

[0038] NR²R³, NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group;

[0039] OR⁴ comprises a free or functionally modified hydroxy group;

[0040] Hal is F, Cl, Br, or I;

[0041] R²⁰ is H, alkyl, acyl;

[0042] R²¹ is H or a pharmaceutically acceptable cation, or COSR²¹ formsa pharmaceutically acceptable thioester moiety;

[0043] A is L₁-A₁-L₂, L₁-A₂-L₂, L₃-A₂-L₄, or L₅-A₂-L₃;

[0044] A₁ is CH₂CH₂;

[0045] A₂ is

[0046] L₁ is CH₂-B-D;

[0047] B and D are the same or different and are CH₂CH₂, CH═CH, or C≡C;

[0048] L₂ is CH₂-K-CH₂CH₂;

[0049] K is CH₂CH₂, CH═CH, or C≡C;

[0050] L₃ is CH₂CH₂CH₂, CH₂CH═CH, CH₂C≡C, CH═CHCH₂, C≡CCH₂, or CH═C═CH;

[0051] L₄ is X-CH₂CH₂;

[0052] X is CH₂CH₂CH═CH, CH₂CH₂C≡C, CH₂CH₂CH₂CH₂, CH₂CH═CHCH₂,CH₂C≡CCH₂, CH═CHCH₂CH₂, C≡CCH₂CH₂, CH₂CH═C═CH, or CH═C═CHCH₂;

[0053] L₅ is CH₂CH₂-B-D; and

[0054] Y is C(O) (i.e. a carbonyl group) or Y is

[0055] or;

[0056] wherein

[0057] R⁹O constitutes a free or functionally modified hydroxy group;

[0058] VI:

[0059] wherein:

[0060] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

[0061] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0062] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0063] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl or aryl;

[0064] Hal is F, Cl, Br or I;

[0065] SR²⁰ comprises a free or functionally modified thiol group;

[0066] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0067] X is C₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenyl group;

[0068] Y is H, free or functionally modified hydroxy group, halo,trihalomethyl, free or functionally modified amino group, free orfunctionally modified thiol group, C(O)R⁷, or alkyl;

[0069] R⁷ is H, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino;

[0070] A is a direct bond or C₁₋₃ alkyl;

[0071] B is CH₂CH₂, cis- or trans-CH═CH, or C≡C; and

[0072] one of D and D¹ is H and the other is a free or functionallymodified OH group, or DD¹ together comprises a double bonded oxygen;

[0073] wherein:

[0074] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

[0075] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0076] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R²and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0077] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl or aryl;

[0078] Hal is F, Cl, Br or I;

[0079] SR²⁰ comprises a free or functionally modified thiol group;

[0080] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0081] E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH; or E is trans-CH═CH and D isCH(OH) in either configuration, wherein the OH is free or functionallymodified; or E is CH₂CH₂ and D is a direct bond;

[0082] p is 1 or 3 when E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH, or when E istrans-CH═CH and D is CH(OH) in either configuration, wherein the OH isfree or functionally modified; or p is 0 when E is CH₂CH₂ and D is adirect bond;

[0083] G-T is CH₂CH₂, CH(SR⁷)CH₂ or trans-CH═CH;

[0084] R⁷ is H, alkyl, aryl, aralkyl, cycloalkyl or acyl;

[0085] Y is CH(OH) in either configuration, in which the OH is free offunctionally modified, or C═O (i.e., a carbonyl group);

[0086] n is 0, 2 or 4; and

[0087] Z is CH₃, CO₂R, CONR²R³ or CH₂OR⁴;

[0088] wherein:

[0089] R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein:

[0090] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0091] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0092] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

[0093] Hal is F, Cl, Br or I;

[0094] SR²⁰ comprises a free or functionally modified thiol group;

[0095] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0096] n is 0 or 2;

[0097] X is O, S(O)_(p), NR⁷ or CH₂, with the proviso that X cannot beCH₂ when n is 0;

[0098] p is 0, 1 or 2;

[0099] NR⁷ comprises a free or functionally modified amino group, e.g.,R⁷ is H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,

[0100] A-B, D-E, G-T and J-K are the same or different and are CH₂CH₂,CH═CH or C≡C, with the proviso that at least one of A-B, D-E, G-T andJ-K must be CH═CH or C≡C; and

[0101] Y is C(O) (i.e., a carbonyl), or Y is

[0102] wherein

[0103] R⁹O constitutes a free or functionally modified hydroxy group;

[0104] wherein:

[0105] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

[0106] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0107] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0108] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

[0109] Hal is F, Cl, Br or I;

[0110] SR²⁰ comprises a free or functionally modified thiol group;

[0111] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0112] A, B, C and D are the same or different and are C₁-C₅ alkyl,alkenyl, or alkynyl or a C₃-C₅ allenyl group;

[0113] X is C(O) (i.e. a carbonyl group) or X is

[0114] wherein

[0115] R⁹O constitutes a free or functionally modified hydroxy group;

[0116] wherein:

[0117] R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein:

[0118] R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

[0119] NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

[0120] OR⁴ comprises a free or functionally modified hydroxy group,e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

[0121] Hal is F, Cl, Br or I;

[0122] SR²⁰ comprises a free or functionally modified thiol group;

[0123] R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

[0124] n is 0 or 2;

[0125] A, B, C and D is C₁-C₅ alkyl, alkenyl, or alkynyl or a C₃-C₅allenyl group;

[0126] Y is

[0127] wherein

[0128] R⁸ is H or CH₃, and

[0129] X is CH₂, CH(CH₃) or C(CH₃)₂; or

[0130] Y is CH₂, CH(CH₃) or C(CH₃)₂, and X is

[0131] wherein

[0132] R⁸ is H or CH₃, with the proviso that Y cannot be CH₂ when X is

[0133] and

[0134] R⁷O comprises a free or functionally modified hydroxy group; and

[0135] wherein:

[0136] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where:

[0137] R is H or a pharmaceutically acceptable cation, or CO₂R forms apharmaceutically acceptable ester moiety;

[0138] NR²R³, NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group;

[0139] OR⁴ comprises a free or functionally modified hydroxy group;

[0140] Hal is F, Cl, Br, or I;

[0141] SR²⁰ comprises a free or functionally modified thiol group;

[0142] R²¹ is H or a pharmaceutically acceptable cation, or COSR²¹ formsa pharmaceutically acceptable thioester moiety;

[0143] A, B, C, D are the same or different and are C₁-C₅ alkyl, C₂-C₅alkenyl, C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group;

[0144] E is

[0145] where

[0146] OR⁷ comprises a free or functionally modified hydroxy group;

[0147] X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and

[0148] Y=a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, acyl, or a free or functionally modified hydroxy, amino,or thiol group; or

[0149] X-Y=(CH₂)_(p)Y¹; where p=0-6; and

[0150] wherein:

[0151] W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q), CH═N,or CH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl;

[0152] Z=H, alkyl, acyl, halo, trihalomethyl, or a free or functionallymodified amino, thiol, or hydroxy group; and

[0153] ____=single or double bond;

[0154] or X-Y=cyclohexyl.

[0155] Preferred HETE derivatives include the compounds of formulasI-III wherein X is a pharmaceutically acceptable salt containing acation selected from the group consisting of: Na⁺; K⁺; Li⁺; Cs⁺; and(A)₄N⁺; and A is independently H, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring.

[0156] Included within the scope of the present invention are theindividual enantiomers of the HETE derivatives, as well as their racemicand non-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A.M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

[0157] The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxy-carbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

[0158] The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl-, or hydroxy-amino group, wherein the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriategroup is substituted for one or both of the hydrogens; an amide, inwhich an acyl group is substituted for one of the hydrogens; acarbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynyl-carbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

[0159] The term “free thiol group” means an SH. The term “functionallymodified thiol group” means an SH which has been functionalized to form:a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; or a thioester, in which an acyl groupis substituted for the hydrogen. Preferred moieties include SH,SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃.

[0160] The term “acyl” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond toanother carbon atom.

[0161] The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

[0162] The term “cycloalkyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more rings, which can be fused or isolated. The rings may besubstituted with other groups, such as halogen, hydroxyl, aryl, aryloxy,alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

[0163] The term “C₁-C₅ cyclopropyl” means an alkyl chain of 1 to 5carbon atoms containing a cyclopropyl group wherein the cyclopropylgroup may start, be contained in or terminate the alkyl chain.

[0164] The term “heterocycloalkyl” refers to cycloalkyl rings thatcontain at least one heteroatom such as O, S, or N in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl.Preferred heterocycloalkyl groups include pyrrolidinyl,tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.

[0165] The term “alkenyl” includes straight or branched chainhydrocarbon groups having 1 to 15 carbon atoms with at least onecarbon-carbon double bond, the chain being optionally interrupted by oneor more heteroatoms. The chain hydrogens may be substituted with othergroups, such as halogen. Preferred straight or branched alkenyl groupsinclude, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

[0166] The term “cycloalkenyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more non-aromatic rings containing a carbon-carbon doublebond, which can be fused or isolated. The rings may be substituted withother groups, such as halogen, hydroxyl, alkoxy, or lower alkyl.Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

[0167] The term “heterocycloalkenyl” refers to cycloalkenyl rings whichcontain one or more heteroatoms such as O, N, or S in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl.Preferred heterocycloalkenyl groups include pyrrolidinyl,dihydropyranyl, and dihydrofuranyl.

[0168] The term “carbonyl group” represents a carbon atom double bondedto an oxygen atom, wherein the carbon atom has two free valencies.

[0169] The term “aminocarbonyl” represents a free or functionallymodified amino group bonded from its nitrogen atom to the carbon atom ofa carbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

[0170] The term “lower alkyl” represents alkyl groups containing one tosix carbons (C₁-C₆).

[0171] The term “halogen” represents fluoro, chloro, bromo, or iodo.

[0172] The term “aryl” refers to carbon-based rings which are aromatic.The rings may be isolated, such as phenyl, or fused, such as naphthyl.The ring hydrogens may be substituted with other groups, such as loweralkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl,3-chlorophenyl, and 4-fluorophenyl.

[0173] The term “heteroaryl” refers to aromatic hydrocarbon rings whichcontain at least one heteroatom such as O, S, or N in the ring.Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with openvalency may be substituted with other groups, such as lower alkyl orhalogen. Examples of heteroaryl groups include imidazole, pyridine,indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline,dihydrobenzofuran, and dihydrobenzindole.

[0174] The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group, respectively, attached through anoxygen linkage.

[0175] The terms “alkoxycarbonyl”, “aryloxycarbonyl”,“heteroaryloxycarbonyl”, “cycloalkoxycarbonyl”,“heterocycloalkoxycarbonyl”, “alkenyloxycarbonyl”,“cycloalkenyloxycarbonyl”, “heterocycloalkenyloxycarbonyl”, and“alkynyloxycarbonyl” represent an alkoxy, aryloxy, heteroaryloxy,cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy,heterocycloalkenyloxy, or alkynyloxy group, respectively, bonded fromits oxygen atom to the carbon of a carbonyl group, the carbonyl groupitself being bonded to another atom through its carbon atom.

[0176] According to the methods of the present invention a HETEderivative of formulas I-XI is applied intraocularly in connection withintraocular surgery. The compositions used in the methods of the presentinvention comprise a pharmaceutically effective amount of one or moreHETE derivatives of formulas I-XI and a pharmaceutically acceptablecarrier. Suitable pharmaceutical carriers are those that can be used inconnection with intraocular surgery and include, but are not limited to,ophthalmically acceptable surgical irrigating solutions andophthalmically acceptable viscoelastic materials. Many such irrigatingsolutions and viscoelastic materials are known. Examples of irrigatingsolutions include, but not limited to, BSS® and BSS PLUS® irrigatingsolutions (Alcon Laboratories, Inc.). Examples of viscoelastics include,but are not limited to, CELLUGEL®, VISCOAT® and PROVISC® viscoelastics(Alcon Laboratories, Inc.) and HEALON® and HEALON® GV viscoelastics(Pharmacia Corporation).

[0177] As used herein, the term “pharmaceutically effective amount”refers to an amount of one or more compounds of formula (I) that, whenadministered to a patient, protects or helps maintain the cornealendothelium. Generally, the compounds of formula (I) will be containedin a composition of the present invention in a concentration range ofabout 0.00001 to 10 percent weight/volume (“% w/v”). Preferably, thecompositions will contain one or more compounds of formula (I) in aconcentration of from about 0.00001-0.01% w/v.

[0178] In one embodiment, the compositions of the present invention willalso contain ethanol. As used herein, “an effective concentration ofethanol” refers to a concentration that enhances the biological efficacyof the formula (I) compositions in vivo. In general, the concentrationof ethanol necessary for the enhancement of the compounds of formula (I)is believed to be somewhat proportional to the concentration of theformula (I) compound(s) administered. If a relatively high concentrationof formula (I) compound(s), e.g., above 0.1% w/v, is administered, theconcentration of ethanol in such compositions may be proportionally lessthan analogous compositions containing lower concentrations of formula(I) compounds. In general, however, the ethanol concentration containedin the ophthalmic compositions of the present invention will range fromabout 0.001-2% w/v. Compositions containing formula (I) concentrationsof about 0.00001-0.05% w/v preferably will contain ethanol in aconcentration of about 0.005-0.40% w/v, and most preferably, about0.02-0.20% w/v.

[0179] Various tonicity agents may be included in the compositions ofthe present invention to adjust tonicity, preferably to that of naturaltears for ophthalmic compositions. For example, sodium chloride,potassium chloride, magnesium chloride, calcium chloride, dextroseand/or mannitol may be added to the composition to approximatephysiological tonicity. Such an amount of tonicity agent will vary,depending on the particular agent to be added. In general, however, thecompositions will have one or more tonicity agents in a totalconcentration sufficient to cause the composition to have an osmolalityof about 200-400 mOsm.

[0180] An appropriate buffer system (e.g., sodium phosphate, sodiumacetate, sodium citrate, sodium borate or boric acid) may be added tothe compositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed. Ingeneral, however, the buffering agent will be present in an amountsufficient to hold the pH within the range 6.5-8.0, preferably 6.8-7.6.

[0181] Antioxidants may be added to compositions of the presentinvention to protect the formula (I) compounds from oxidation duringstorage and/or or to provide antioxidant effects in the eye. Examples ofsuch antioxidants include, but are not limited to, vitamin E and analogsthereof, ascorbic acid and derivatives, and butylated hydroxyanisole(BHA).

[0182] The following examples are presented to illustrate variousaspects of the present invention, but are not intended to limit thescope of the invention in any respect.

EXAMPLE 1

[0183] Two-part Irrigating Solution (Use within 6 Hours ofReconstitution): Ingredient Concentration (% w/v) Part I (approx. 480mL) HETE derivative 0.00001-0.01 NaCl 0.7-0.8 KCl 0.03-0.04 DibasicSodium Phosphate 0.04-0.05 Sodium Bicarbonate 0.2-0.3 HCl/NaOH pH adjustto 7.4 Water for injection qs 100 Part II (approx. 20 mL) GlutathioneDisulfide 0.4-0.5 Calcium Chloride (Dihydrate) 0.3-0.4 MagnesiumChloride (Hexahydrate) 0.4-0.6 Dextrose (Anhydrous) 2-3 Water forinjection qs 100

Example 2

[0184] Viscoelastic Composition: Ingredient Concentration (% w/v) HETEderivative 0.00001-0.01 Sodium Chondroitin Sulfate 3.5-4 Hyaluronic Acid(Sodium Salt) 2.9-3 NaCl 0.3-0.5 Dibasic Sodium Phosphate (Anhydrous)0.15-0.25 Monobasic Sodium Phosphate (Monohydrate) 0.04-0.05 HCl/NaOH pHadjust to 7.4 Water for injection qs 100

[0185] The invention in its broader aspects is not limited to thespecific details shown and described above. Departures may be made fromsuch details within the scope of the accompanying claims withoutdeparting from the principles of the invention and without sacrificingits advantages.

What is claimed is:
 1. A method of maintaining and protecting thecorneal endothelium during intraocular surgery comprising theintraocular application of a composition comprising one or more HETEderivatives.
 2. The method of claim 1 wherein the HETE derivative is acompound of the formula

wherein X is OR or NHR; R is H, a cationic pharmaceutically acceptablesalt moiety, substituted or unsubstituted alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is madewith a moiety selected from the group consisting of: alkyl, halogen,hydroxy and functionally modified hydroxy; R′ is H, substituted orunsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl,wherein the substitution is made with a moiety selected from the groupconsisting of: alkyl, halogen, hydroxy and functionally modifiedhydroxy; and Y is

wherein R″ is H or C(O)R.
 3. The method of claim 2 wherein R is selectedfrom the group consisting of: Na⁺; K⁺; Li⁺; Cs⁺; and (A)₄N⁺; and A isindependently H, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring.
 4. The methodof claim 1 wherein the composition is selected from surgical irrigatingsolutions and viscoelastic compositions.
 5. The method of claim 1wherein the HETE derivative is present in the composition in aconcentration range of about 0.00001 to 10% w/v.
 6. The method of claim5 wherein the concentration range is about 0.00001-0.01% w/v.
 7. Themethod of claim 1 wherein the composition comprises ethanol.
 8. Anirrigating solution intended for use during intraocular surgerycomprising an ophthalmically acceptable irrigating fluid and a HETEderivative.
 9. A viscoelastic composition intended for use duringintraocular surgery comprising an ophthalmically acceptable viscoelasticmaterial and a HETE derivative.